Obesity is an increasingly prevalent disorder of the system for regulating energy balance that has major morbid consequences. The physiologic regulation of energy balance and body weight involves hypothalamic neural circuits that respond to peripheral hormones, including the adipocyte hormone leptin and the beta cell hormone insulin. Nearly all rodent and human obesity is characterized by resistance to the actions of leptin and insulin. Although the mechanisms causing resistance are not well understood, these pathways are likely responsible in significant measure for susceptibility to obesity and diabetes, and antagonizing the pathways causing leptin and insulin resistance would likely yield substantial therapeutic benefit. Suppressor of cytokine signaling 3 (SOCS3) is a molecule that is induced by leptin and insulin in cells and tissues, is increased in expression in tissues of obese animals, and is capable of antagonising signaling by both leptin and insulin. It is therefore a potential molecular mediator of both obesity and diabetes. The goal of this proposal is to determine the biological function of SOCS3 as a negative regulator of insulin and leptin signaling and action in the brain of normal and obese mice. In specific aim 1, we will attempt to understand the role of SOCS3 in leptin signaling and action in the CMS, using mice with conditional deletion of SocsS in neurons. We will determine the consequences of neuronal deletion of SOCSS for leptin signaling in hypothalamus, leptin actions on food intake, energy expenditure and glucose homeostasis, and leptin action on AMPK activity in hypothalamus and peripheral tissues. In aim 2, we will attempt similar experiments to clarify the role of SOCSS in regulating insulin action in the CMS. In aim 3, we will create models in which SOCSS is either overexpressed, or deleted, from POMC and AgRP neurons, to determine the specific role of SOCSS in the function of these neurons in energy balance.